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However, its potential role in Alzheimer's disease (AD), especially in modulating receptor\u2010interacting protein kinase 1 (RIPK1)\u2010mediated neuroinflammation and necroptosis, remains unclear. This study aimed to investigate Ori's therapeutic mechanism in AD by targeting RIPK1. We utilized cellular thermal shift assay (CETSA), drug affinity responsive target stability assay (DARTS), and bio\u2010layer interferometry (BLI) to verify the binding of Ori to RIPK1. In\u00a0vitro, inflammatory and necroptotic responses were assessed in BV2 microglial cells and HT22 neuronal cells using enzyme\u2010linked immunosorbent assay (ELISA), reverse transcription quantitative polymerase chain reaction (RT\u2010qPCR), Western blotting, immunofluorescence, and flow cytometry assays. In\u00a0vivo, we evaluated Ori's therapeutic efficacy in 5\u00d7\u2009FAD transgenic mice, a well\u2010established AD model, through behavioral analysis using the Morris water maze, along with histological and biochemical assessments of brain tissues. Ori demonstrated a robust interaction with RIPK1 (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>D<\/jats:sub>\n                    \u2009=\u2009533\u2009nM) and significantly increased its thermal and proteolytic stability. Treatment with Ori markedly suppressed the secretion of pro\u2010inflammatory cytokines interleukin\u20106 (IL\u20106) and tumor necrosis factor alpha (TNF\u03b1) in microglia by inhibiting the RIPK1\u2013ERK1\/2\u2013NF\u2010\u03baB signaling pathway. In neurons, Ori effectively blocked the activation of the RIPK1\u2013RIPK3\u2013MLKL signaling cascade, prevented necrosome formation, and significantly reduced necroptotic cell death. Importantly, in the 5\u00d7\u2009FAD mouse model, Ori treatment substantially improved spatial learning and memory performance, decreased amyloid\u2010beta (A\u03b2) plaque deposition, and attenuated inflammatory and necroptotic markers in both cortical and hippocampal regions. Ori as a natural small\u2010molecule inhibitor of RIPK1, capable of concurrently mitigating neuroinflammation and necroptosis\u2014two critical pathological processes underpinning AD. These findings strongly support Ori's potential as a disease\u2010modifying therapeutic for AD.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70185","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T12:54:54Z","timestamp":1770900894000},"page":"2270-2287","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Oridonin Ameliorates Alzheimer's Disease\u2010Like Pathology in Male Mice Through Inhibition of Receptor\u2010Interacting Protein Kinase 1"],"prefix":"10.1002","volume":"40","author":[{"given":"Yuting","family":"Li","sequence":"first","affiliation":[{"name":"College of Medical Technology, State Key Laboratory of Southwestern Chinese Medicine Resources, the Innovative Institute of Chinese Medicine and Pharmacy Chengdu University of Traditional Chinese Medicine  Chengdu 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and Pharmacy Chengdu University of Traditional Chinese Medicine  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Medical Technology, State Key Laboratory of Southwestern Chinese Medicine Resources, the Innovative Institute of Chinese Medicine and Pharmacy Chengdu University of Traditional Chinese Medicine  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Guo","sequence":"additional","affiliation":[{"name":"College of Medical Technology, State Key Laboratory of Southwestern Chinese Medicine Resources, the Innovative Institute of Chinese Medicine and Pharmacy Chengdu University of Traditional Chinese Medicine  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunguo","family":"Jiang","sequence":"additional","affiliation":[{"name":"College of Medical Technology, State Key Laboratory of Southwestern 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